The overall goal of our work is to establish the potency and efficacy of a novel 2-adrenergic receptor agonist (compound 49b) in the prevention and/or reversal of non-proliferative diabetic retinopathy. Diabetic retinopathy is the leading cause of blindness in working age adults. The current treatment paradigm for retinopathy patients has not changed significantly since laser photocoagulation became popular in the 1970's. Work needs to be completed to develop a novel treatment for diabetic retinopathy that prevents the progression of the disease from the non-proliferative form to the proliferative form. We have data demonstrating that elimination of sympathetic neurotransmission to the rat retina reproduces the biochemical and histological features of non-proliferative diabetic retinopathy, which were reproduced when rats were treated with a beta-adrenergic receptor antagonist. We have now demonstrated both in vitro and in vivo that maintenance of beta- adrenergic receptor signaling in the diabetic rat retina can inhibit the loss of retinal function and morphology. This maintenance of visual function was associated with a decreased level of inflammatory cytokines and increased insulin receptor signaling. Unfortunately, topical isoproterenol has a narrow dose range and is not a commercially viable product. The projects in this proposal will test a novel beta-adrenergic receptor agonist for topical application to prevent/reverse experimental non-proliferative retinopathy. In this phase 1 STTR, we will demonstrate acute efficacy, pharmacokinetics, and potency of compound 49b in cell culture and in diabetic rats. Translation of this work into patient care will be expedited, as functional studies on the diabetic rodents will mirror those studies that occur in human subjects. The use of chemically novel compounds will allow for increased interest from both industry and federal funding. The deliverables from this project are pre-IND enabling data that will facilitate movement of Compound 49b into FDA approval and human clinical trials. PUBLIC HEALTH RELEVANCE: The work proposed in this study will test a novel therapeutic agent to prevent/treat diabetic retinopathy using topical application. The proposed studies will demonstrate efficacy, safety and potency of compounds 49b to inhibit diabetic retinopathy